Molecular basis of fosmidomycin's action on the human malaria parasite Plasmodium falciparum

The human malaria parasite Plasmodium falciparum is responsible for the deaths of more than a million people each year. Fosmidomycin has been proven to be efficient in the treatment of P. falciparum malaria by inhibiting 1-deoxy-D-xylulose 5-phosphate reductoisomerase (DXR), an enzyme of the non-mevalonate pathway, which is absent in humans. However, the structural details of DXR inhibition by fosmidomycin in P. falciparum are unknown. Here, we report the crystal structures of fosmidomycin-bound complete quaternary complexes of PfDXR. Our study revealed that (i) an intrinsic flexibility of the PfDXR molecule accounts for an induced-fit movement to accommodate the bound inhibitor in the active site and (ii) a cis arrangement of the oxygen atoms of the hydroxamate group of the bound inhibitor is essential for tight binding of the inhibitor to the active site metal. We expect the present structures to be useful guides for the design of more effective antimalarial compounds

Fosmidomycin Uptake into Plasmodium and Babesia-Infected Erythrocytes Is Facilitated by Parasite-Induced New Permeability Pathways

., a mouse malaria parasite. and related parasites. Our data provide further evidence that parasite-induced new permeability pathways may be exploited as routes for drug delivery

Connexin43 Modulates Cell Polarity and Directional Cell Migration by Regulating Microtubule Dynamics

Knockout mice deficient in the gap junction gene connexin43 exhibit developmental anomalies associated with abnormal neural crest, primordial germ cell, and proepicardial cell migration. These migration defects are due to a loss of directional cell movement, and are associated with abnormal actin stress fiber organization and a loss of polarized cell morphology. To elucidate the mechanism by which Cx43 regulates cell polarity, we used a wound closure assays with mouse embryonic fibroblasts (MEFs) to examine polarized cell morphology and directional cell movement. Studies using embryonic fibroblasts from Cx43 knockout (Cx43KO) mice showed Cx43 deficiency caused cell polarity defects as characterized by a failure of the Golgi apparatus and the microtubule organizing center to reorient with the direction of wound closure. Actin stress fibers at the wound edge also failed to appropriately align, and stabilized microtubule (Glu-tubulin) levels were markedly reduced. Forced expression of Cx43 with deletion of its tubulin-binding domain (Cx43dT) in both wildtype MEFs and neural crest cell explants recapitulated the cell migration defects seen in Cx43KO cells. However, forced expression of Cx43 with point mutation causing gap junction channel closure had no effect on cell motility. TIRF imaging revealed increased microtubule instability in Cx43KO cells, and microtubule targeting of membrane localized Cx43 was reduced with expression of Cx43dT construct in wildtype cells. Together, these findings suggest the essential role of Cx43 gap junctions in development is mediated by regulation of the tubulin cytoskeleton and cell polarity by Cx43 via a nonchannel function

Designing business models of cloud platforms

Cloud computing and its three facets (Software as a Service (SaaS), Platform as a Service (PaaS), and Infrastructure as a Service (IaaS)) are terms that denote new developments in the software industry. In particular, PaaS solutions, also referred to as cloud platforms, are changing the way software is being produced, distributed, consumed, and priced. Software vendors have started considering cloud platforms as a strategic option but are battling to redefine their offerings to embrace PaaS. In contrast to SaaS and IaaS, PaaS allows for value co-creation with partners to develop complementary components and applications. It thus requires multisided business models that bring together two or more distinct customer segments. Understanding how to design PaaS business models to establish a flourishing ecosystem is crucial for software vendors. This doctoral thesis aims to address this issue in three interrelated research parts. First, based on case study research, the thesis provides a deeper understanding of current PaaS business models and their evolution. Second, it analyses and simulates consumers' preferences regarding PaaS business models, using a conjoint approach to find out what determines the choice of cloud platforms. Finally, building on the previous research outcomes, the third part introduces a design theory for the emerging class of PaaS business models, which is grounded on an extensive action design research study with a large European software vendor. Understanding PaaS business models from a market as well as a consumer perspective will, together with the design theory, inform and guide decision makers in their business model innovation plans. It also closes gaps in the research related to PaaS business model design and more generally related to platform business models

Designing Business Models for Cloud Platforms

Platform as a Service (PaaS) has become a strategic option for software vendors who expect to benefit from value co-creation with partners by developing complementary components and applications. In reality, however, established and new software vendors are battling to redefine their offering to embrace PaaS. They face the challenges of transforming, configuring, and calibrating their PaaS business models to align them with existing business models, customer expectations, and competitive pressures. This motivates our research question: How can software providers design viable business models for Platform as a Service? Our study develops a design theory for PaaS business models. This theory is grounded on a 12-month action design research study at one of the largest global software companies (here called Alpha) with mixed PaaS experiences in the past. Our research's primary contribution is a set of design principles that guide software providers to define a viable PaaS business model in order to create a flourishing software ecosystem for their cloud platform. By synthesizing prescriptive knowledge related to business model design for emerging cloud platforms, our study advances PaaS research towards the existing body of research on software platforms and business models

User-Oriented Cloud Service Design Based on Market Research Technologies

For the IT industry, cloud computing has a disruptive effect, since it fundamentally changes how IT resources are produced, distributed, consumed, and priced. Designing cloud services remains a challenge, as the markets are very dynamic and cloud users are heterogeneous, locally distributed and not within the reach of the organization. This research-in-progress paper suggests the use of market research techniques, namely conjoint analysis, in the requirements elicitation process for cloud services. The contribution is a method component that extends existing requirements engineering methods. It supports cloud service providers in addressing specific questions of cloud service design: to analyse user preferences and the many trade-offs between different functional, non-functional and economic properties, to identify customer segments and develop tailored offerings, to analyse willingness-to-pay for specific features and to simulate market reactions of new designs

A Method for Simulating Cloud Business Models: A Case Study on Platform as a Service

Cloud computing has changed how software is produced, distributed, consumed, and priced. The cloud paradigm has had a disruptive effect on existing business models and elicited a need for more thoroughly defined business models as well as the tools to represent and compare business models. In this paper, we address this research gap and present a structured approach that allows a systematic design of business models for cloud computing and provides tools to facilitate the business model design process through simulation. The resulting method is specified by means of a meta-model as well as a procedure model and is demonstrated by a software prototype. The developed method has been evaluated in three case studies in the context of Platform as a Service business models